期刊
NATURE
卷 606, 期 7912, 页码 180-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41586-022-04747-5
关键词
-
资金
- NIH [R35GM143097, R01GM107710, R01GM118939, R35GM136415, R01GM089740, R01GM137109, R01NS098772, 1S10OD021596]
- UCSF Program for Breakthrough Biomedical Research (PBBR)
- American Heart Association Career Development Award [19CDA34630062]
- American Heart Association [18POST33960587]
Mitochondria generate heat through H+ leakage mediated by UCP1 and AAC. Protonophores induce H+ leakage, but their clinical application is limited. This study directly measured the effect of protonophores on H+ leakage and found that it is dependent on AAC and UCP1. Through molecular structure analysis and mathematical modeling, a mechanism of uncoupler-dependent H+ leakage through AAC is proposed.
Mitochondria generate heat due to H+ leak (I-H) across their inner membrane(1). I-H results from the action of long-chain fatty acids on uncoupling protein 1 (UCP1) in brown fat(2-6) and ADP/ATP carrier (AAC) in other tissues(1,7-9), but the underlying mechanism is poorly understood. As evidence of pharmacological activators of I-H through UCP1 and AAC is lacking, I-H is induced by protonophores such as 2,4-dinitrophenol (DNP) and cyanide-4-(trifluoromethoxy) phenylhydrazone (FCCP)(10,11). Although protonophores show potential in combating obesity, diabetes and fatty liver in animal models(12-14), their clinical potential for treating human disease is limited due to indiscriminately increasing H+ conductance across all biological membranes(10,11) and adverse side effects(15). Here we report the direct measurement of I-H induced by DNP, FCCP and other common protonophores and find that it is dependent on AAC and UCP1. Using molecular structures of AAC, we perform a computational analysis to determine the binding sites for protonophores and long-chain fatty acids, and find that they overlap with the putative ADP/ATP-binding site. We also develop a mathematical model that proposes a mechanism of uncoupler-dependent I-H through AAC. Thus, common protonophoric uncouplers are synthetic activators of I-H through AAC and UCP1, paving the way for the development of new and more specific activators of these two central mediators of mitochondrial bioenergetics.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据